Stromal cells and immune cells in different organ microenvironments have optimized organ-specific immune responses that could limit metastasis formation and control disease-induced inflammation. The liver receives venous blood from the gastrointestinal tract, thereby setting up a unique environment where the host immune system interacts with potential foreign pathogens. Thus immune responses in the liver are tightly regulated to prevent chronic activation while maintaining the ability to react quickly to pathogens. Chronic liver insult from uncontrolled infection or inflammatory mediators are underlying causes to the initiation and progression of hepatic tumors. NKT cells, which are concentrated in the liver, respond rapidly to antigenic and cytokine activation inducing critical bystander activation of adaptive and innate cells to resolve infection and resist tumor growth. We are currently examining the molecules that facilitate the interaction between NKT cells and other hepatic cells that may be important in regulating the type and magnitude of a local immune response. In our previous study, we found that NKT cells were cleared in the liver following activation and that chronic activation of NKT cells with IL-12 and IL-18 or the antigen alpha-galactosylceramide (AlphaGalCer) causes systemic loss of NKT cells requiring thymic development for repopulation. The NKT cells that repopulate the liver following activation-induced ablation have altered response to subsequent antigenic activation. We are currently assessing how altered NKT cell responses affect the development and progression of tumors induced by oncogenes in the liver. These studies will also help us assess whether the altered response of NKT cells following activation-induced ablation is the result of changes in effector molecules critical in the bystander activation of tumor responding CD8 and NK cells. These data reveal that inflammatory signals can alter the liver microenvironment by inducing long-term changes in NKT cells function. Numerous studies have examined how NKT cells limit tumor growth following activation with IL-12 or AlphaGalCer. However, the natural role of NKT cell in controlling tumor progression in the liver has not been characterized. Using oncogenes to initiate tumors in the liver, we examined the role of NKT cells in limiting tumor growth. We observed differences in the regulation of tumor growth between mice deficient in all NKT cells or only Type I NKT cells. While mice deficient in all NKT cells had decreased survival, from tumor burden, those lacking Type I NKT cells survived longer. These studies suggest NKT cells subsets counter-regulate each other in the control of tumors developing in the liver. Studies are underway to determine how different subsets of NKT cells control tumor growth and at what stage of development they may be involved in tumor progression. By affecting the function of NKT cells with immunotherapy, we aim to achieve a shift in the natural anti-tumor response in the liver. Additionally, we are investigating how Type I NKT cells regulate Type II NKT cells during tumor progression in the liver and how inflammatory signals that induce long-term functional changes in NKT cells affect the regulatory balance between Type I and Type II NKT cells.